tbuckley/cabot-search huggingface dataset:
Agreement between FGFR2 immunohistochemistry assays and fluorescence in situ hybridization (FISH) in metastatic gastric cancer: A comparison study.
Authors: Grigory A. Raskin, Marina S. Mukhina, Elena D. Kravtsova, Sergei Tjulandin, Ilya Tsimafeyeu
Journal: Journal of Clinical Oncology (2023)

301 Background: FGFR2 status of a patient with metastatic gastric adenocarcinoma could be an important factor in determining optimal treatment strategy with FGFR2 inhibitors and antibodies. The question remains how well different assays agree on the FGFR2 status of the same patient and whether one test can be substituted by another. Methods: Pairwise comparison of 4 tests based on the same patient population was performed: 3 IHC assays [Abcam clone EPR24075-418, R&amp;D clone 98706, Santa Cruz clone C-8] and one FISH test. One hundred and nine formalin-fixed, paraffin embedded samples (including 64 primary tumors and 45 metastases of same patients) were obtained and were stained with FGFR2 IHC assays. Two trained pathologists independently evaluated the percentages of tumor staining and their intensity. FGFR2 FISH was performed as described previously [Su, BJC 2014]. The concordance analysis was performed to assess (1) correlation of FGFR2 expression/amplification between different assays in primary and metastases, (2) the predictive properties of one test of another. Results: After evaluating the expression in the first 19 patients, further study was carried out only using the Abсam assay due to pronounced nuclear staining with other IHC tests. FGFR2 any level expression was detected in 29 (47%) primary tumors and 18 (40%) metastases with concordance of 91%. The prevalence of FGFR2 amplification was 9.4% and intratumoral heterogeneity was observed in 33% of FGFR2 amplified cases. Pearson Correlation Coefficients (PCC) were: 0.89, 0.38 and 0.35 between IHC3+/FISH, IHC≥1% stained cells/FISH and IHC≥10%/FISH, respectively. The table represents how well one assay can predict the same outcome (positivity or negativity) of another assay. Conclusions: Among patients who were negative by FISH, 86%-93% of the patients were negative by IHC assay (Abcam). Among patients who were positive by FISH, 75-80% of them were positive by IHC. FISH should not be recommended as a substitute for a FGFR2 IHC assay due to high probability of false negative prediction as a result of intratumoral heterogeneity and low PCC. [Table: see text]
Pressure-Enabled Drug Delivery (PEDD) of a class C TLR9 agonist in combination with checkpoint inhibitor therapy in a murine pancreatic cancer model.
Authors: Benedict Capacio, Jayanth Shankara Narayanan, Diego Vicente, Yujia Liu, Jason LaPorte, Bryan Cox, David Jaroch, Steven Katz, Rebekah Ruth White
Journal: Journal of Clinical Oncology (2023)

729 Background: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma (PDAC). This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent pre-clinical cancer models and early-phase clinical trials have demonstrated the efficacy of toll-like receptor 9 agonists (TLR9a), including the synthetic CpG oligonucleotide SD101, to stimulate innate and adaptive immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure Enabled Drug Delivery (PEDD) via Pancreatic Retrograde Venous Infusion (PRVI) of a TLR9a would improve responsiveness to systemic anti-programmed death receptor-1 (PD-1) checkpoint inhibitor therapy in a murine orthotopic PDAC model. Methods: Murine PDAC (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to PRVI saline (pSAL, n=9), systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (sAPD1, n = 6), 30mcg PRVI TLR9a (pTLR9a, n=9), 30mcg systemic TLR9a (sTLR9a, n=7) on Day 0, and combination 30mcg PRVI TLR9a on Day 0 and systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (COMBO, n =9). Fluorescently-labeled TLR9a (radiant efficiency [RE]) was measured on day 1. Blood and tumors were collected at necropsy 12 days after infusion. Results: All mice survived to necropsy. Site of tumor fluorescence measurements revealed higher intensity fluorescence in pTLR9a compared to sTLR9a (7.5x10^5 vs. 2.4x10^5 RE, p= 0.048). Significantly lower MDSCs in the COMBO vs. pSAL are shown. Tumor weights were significantly lower in the COMBO group compared to pSAL (400 vs. 964 mg, p=0.003), and were also lower, although not significantly, than in the pTLR9a (400 vs. 518mg, p=0.50), and sAPD1 (400 vs. 645 mg, p = 0.70) groups. Conclusions: PEDD of TLR9a by PRVI with systemic anti-PD-1 demonstrated improved PDAC tumor control. These results support study of this combination therapy in PDAC patients and expansion of ongoing PEDD clinical trials. [Table: see text]
A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC).
Authors: Changqing Xie, M. Cecilia Monge B., Donna Mabry-Hrones, Kelley Lauren Coffman, Stephanie Hicks, Bernadette Redd, Brad Wood, Steven Highfill, Mitchell Ho, Tim F. Greten
Journal: Journal of Clinical Oncology (2023)

TPS624 Background: The mortality of hepatocellular carcinoma (HCC) is increasing worldwide, but outcome of systemic treatments in advanced HCC is suboptimal. Adoptive T-cell transfer therapy represents a promising field that exploits the ability of T-cells to recognize and eliminate their target. Targeting the tumor-associated antigen glypican- 3 (GPC3) through chimeric antigen receptors (CAR) engineered T cells is a mechanistically rational novel treatment for advanced HCC. This study aims to determine the dose and early signals of GPC3 targeted (CAR)-T cells in advanced GPC3 expressing HCC (NCT05003895). Methods: This phase I first in human dose escalation trial will study the safety and feasibility of CAR (hYP7)- T cells in advanced HCC patients expressing GPC3. Eligibility criteria includes advanced HCC, not candidates for curative interventions, progressed on first line systemic treatment, tumor GPC3 positivity of ³ 25% by IHC, Child-Pugh Class A, ³1 measurable lesion, ECOG 0 or 1, adequate organ and marrow function. ParticipantsÕ T cells collected through leukapheresis will be transduced with a lentivirus encoding the CAR construct to generate CAR expressing T cells. Patients receive a conditioning chemotherapy regimen of cyclophosphamide and fludarabine prior to the infusion of the GPC3 directed CAR-T cells (Table). The trial has a 4-level modified Fibonacci dose escalation with a minimum of 3 patients at each level and a 28-day interval between the first three patients. Response will be assessed by imaging every two months during the first year. Patients undergo close monitoring with safety assessments during the first year and are followed for life. The primary objective is to determine the MTD, DLT, safety and feasibility of anti-GPC3 CAR expressing T- cells in patients with GPC3-expressing advanced HCC. Secondary objectives include best overall response and overall survival. Exploratory objectives are multiple and include studies to evaluate the persistence and peak levels of anti-GPC3 CAR-T cells after infusion. Recruitment began in December 2021 and the two patients at dose level -1 has been treated; the planned sample size is 38 patients. Table 1 Dose Level Anti-GPC3 CAR-T Cyclophosphamide (mg/m2) Fludarabine (mg/m2) Level -1 0.3x106 CAR-T per kg bw 200 30 Level 1 0.3x106 CAR-T per kg bw 300 30 Level 2 1x106 CAR-T per kg bw 300 30 Level 3 3x106 CAR-T per kg bw 300 30. Clinical trial information: NCT05003895 .
Fruquintinib combined with tislelizumab and SBRT as a later-line therapy in microsatellite stability (MSS) metastatic colorectal cancer (mCRC): Results from the FRUIT trial.
Authors: Xianglin Yuan, Mingsheng Zhang, Huiying Hou
Journal: Journal of Clinical Oncology (2023)

150 Background: MSS patients (pts) account for the majority of all CRC pts and show poor response to immunotherapy. While fruquintinib plus PD-1 inhibitors is an effective option for MSS CRC pts in China who are refractory to multiple lines of therapy. In addition, immunomodulatory effects of stereotatic body radiotherapy (SBRT) have demonstrated in previous studies. Here, we report FRUIT trial of fruquintinib combined with tislelizumab and SBRT as a later-line therapy in MSS mCRC pts. Methods: In this single-arm, open-label, single-center, phase II trial (NCT04924179), we included mCRC pts who have failed with at least second-line therapy. Eligible pts undergo the following regimens on a 21-days cycle: fruquinitib (5mg, QD, PO, d1-14) plus tislelizumab (200mg, d1, I.V.) and SBRT (8-10Gy×5F, QOD). The primary endpoint is progression-free survival (PFS), and secondary endpoints are disease-control rate (DCR), objective response rate (ORR), overall survival (OS), and safety. The responses are evaluated according to RECIST Version 1.1 and adverse events are evaluated by CTCAE v5.0. Results: AS of August 31, 2022, 24 pts were included in the trial and 23 (11 male; media age 60 years; all pts with MSS; 7 had received 3 prior lines of therapy) in the efficacy analysis. 87%, 9% and 17% pts had received bevacizumab, regorafenib and cetuximab in previous therapy, respectively. Among 23 pts, median follow-up was 7.8 mo (95%CI: 4.31, 11.29). The median PFS was 5.1mo (95%CI: 0.57-9.63), with 9 pts still on treatment at data cutoff. 6pts achieved partial response (PR), 13 stable disease (SD), illustrating an ORR of 26% and a DCR of 83%. Adverse events (AEs) occurred in 22 (96%) pts which were mostly grade 1/2. 17% pts experienced a grade 3/4 AEs, including hypertension (9%), hand foot skin reaction (4%) and thrombocytopenia (4%). The combination regimen was well tolerate. Conclusions: Fruquintinib plus tislelizumab and SBRT as a later-line therapy in refractory MSS mCRC pts shows a promising clinical benefit, with a manageable safety profile, which suggests a potential new paradigm for therapy in MSS mCRC pts. Clinical trial information: NCT04924179 .
Role of chemotherapy in clinical T2N0M0 gastric cancer.
Authors: Sawyer Bawek, Yeshwanth Vedire, Adrienne Groman, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2023)

308 Background: The role of chemotherapy for patients with early stage, node-negative gastric adenocarcinoma (T2N0M0) remains unclear. Possible options are surgery alone, surgery followed by adjuvant chemotherapy, or perioperative chemotherapy. The objective of our study was to investigate the role and sequence of chemotherapy in T2N0M0 gastric adenocarcinoma. Methods: The National Cancer Data Base (2006-2017) was used to identify patients with T2N0M0 gastric adenocarcinoma. Patients were categorized into 3 groups, surgery alone (S), surgery followed by adjuvant chemotherapy (AC), and peri-operative chemotherapy (POC). Univariate and multivariable Cox proportional-hazards models were performed to evaluate treatment differences in overall survival (OS). Patients were further sub-categorized into two subgroups based on the number of regional nodes examined, less than 15 (RNE&lt;15) and greater or equal to 15 (RNE&gt;15). Univariate and multivariable Cox proportional-hazards models were performed on each subgroup to assess the treatment differences within two groups. Results: The retrospective study analyzed 3,142 patients between 2006 to 2017. Surgery alone represented 2,090 patients (66.5%), AC group had 360 patients (11.5%), and the POC group 692 patients (22.0%). The median age of the population was 70 yrs. Mean inpatient stay was 12.5 days in S, 9.2 days in AC and 10.1 days in the POC group (p&lt;0.001). In the multivariable model, surgery followed by adjuvant chemotherapy (HR 0.75, p=0.003), RNE&gt;15 (HR 0.73, p&lt;0.001), patients treated at academic facilities (HR 0.84, p=0.005), female sex (HR 0.84, p=0.004), and Asian race (HR 0.69, p=0.002) had better outcomes. There were 1,526 (49.2%) patients with RNE&lt;15 and 1,577 (50.8%) patients with RNE&gt;15. Subgroup analysis showed that peri-operative chemotherapy for RNE&lt;15 was beneficial (HR 0.74, p= 0.029). Patients with RNE&gt;15 had an improved survival with surgery followed by adjuvant chemotherapy (HR 0.72, p= 0.017) in the multivariable model. Conclusions: Surgery followed by adjuvant chemotherapy was found to be beneficial in patients having a T2N0M0 Gastric Cancer. However, the number of lymph nodes examined during surgery influences this association. Perioperative chemotherapy maybe beneficial for patients who were under staged due to inadequate exploration of lymph nodes during surgery.
Nab-paclitaxel plus anti–PD-1 antibody as second-line treatment for advanced biliary tract cancer: An investigator-initiated phase 2 study (NapaSinti trial).
Authors: Xiaofen Li, Nan Zhou, Yu Yang, Hongfeng Gou
Journal: Journal of Clinical Oncology (2023)

564 Background: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. Gemcitabine + cisplatin ±durvalumab is the standard first-line treatment for advanced BTC. But in second-line setting, there is no satisfactory regimen for most patients without specific genetic mutations. This prospective, single-arm, phase 2 study is conducted to investigate the efficacy and safety of second-line nab-paclitaxel combined with sintilimab in advanced BTC patients. Methods: Eligible patients are histologically confirmed local advanced or metastatic adenocarcinoma or cholangiocellular carcinoma in biliary tract; aged from 18 to 75 years; with a performance status and adequate organ function; with documented disease progression after prior gemcitabine or fluorouracil-based systemic chemotherapy; not received taxol drugs or immune checkpoint inhibitors treatment. Enrolled patients will receive nab-paclitaxel 125mg/m 2 on day 1, 8 plus sintilimab 200mg on day 1, administered intravenously every three weeks. The primary end point is objective response rate (ORR). The secondary end points are progression free survival (PFS), overall survival (OS) and adverse reactions. Next-generation sequencing (NGS) is voluntary before treatment. Results: Up to September 2022, 24 BTC patients have been enrolled, including 22 patients available for efficacy evaluation. The ORR is 27.3% (6/22), including 1 complete response (CR) and 5 partial response (PR). Disease control rate is 63.6% (14/22). And median PFS is 5.63 months (95% CI: 1.92-9.35 months). Median OS from enrollment to death of any cause is 12.60 months (95%CI: 7.84-17.36 months). The frequent grade 3 drug-related adverse events are leukopenia (16.7%), anemia (12.5%), neutropenia (8.3%), peripheral neuropathy (8.3%). There is no grade 4 drug-related adverse event occurred. One patient has experienced grade 3 immunological colitis. 11 participants have received NGS testing, with 9 ones are available for efficacy evaluation. Among the 9 participants, 5 patients harbor TP53 mutation [2 evaluated as PR, 2 SD (stable disease) and 1 PD (progressive disease)]; 3 patients harbor genetic mutations associated with DNA damage response pathway (2 evaluated as PR and 1 PD); and 1 patient is in status of microsatellite instability-high (MSI-H) evaluated as PR. Conclusions: The preliminary results of NapaSinti trial propose a brand new and effective regimen as second-line treatment for advanced biliary tract cancer. NGS may become a hopeful tool for efficacy prediction. Clinical trial information: ChiCTR2100052118 .
Clinical and prognostic utility of ALBI versus Child-Pugh score in a Mexican population with hepatocellular carcinoma.
Authors: Maria del Consuelo Diaz Romero, Stefan Zilli Hernandez, German Calderillo Ruiz, Ana Zyanya Xcaret Camacho Sanchez, Berenice Carbajal, Marytere Herrera, Erika Ruiz-Garcia, Sayako Mariana Miyagui-Adame
Journal: Journal of Clinical Oncology (2023)

517 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The assessment of liver function is crucial in determining the prognosis of patients. Aim: To compare the utility of the ALBI and CHILD-PUGH scores in predicting the prognosis and treatment of patients with hepatocellular carcinoma at the National Cancer Institute, Mexico. Methods: Retrospective, observational study. Included patients diagnosed with HCC and treated at the National Cancer Institute 2008-2021. Statistical analysis included: X 2 and t-test, Kaplan Meier, Log Rank, and Cox Regression. Statistical significance was assessed when p was bilaterally &lt;0.05. Results: A total of 315 patients diagnosed with HCC were included, mostly male (61%) with a median age of 67 years, mostly in the advanced stages of the disease (90%). Regarding liver functionality scores, of the patients who were scored in CHILD-PUGH-A5 (n=124), 53% were in ALBI G1, while 47% scored ALBI G2. Regarding the CHILD-PUGH-A6 group (n=92) only 71% of patients scored ALBI G2, and among CHILD-PUGH-B7 score (n=55) patients, only 13% scored in the ALBI G3 group (p&lt;0.001). In survival analysis, CHILD-PUGH-A5 patients had a median OS of 40 months, while CHILD-PUGH-A6 patients showed a median OS of 11 months (p&lt;0.001). Patients with a CHILD-PUGH-B7 score showed a median OS of 10 months compared to patients with a CHILD-PUGH-B8 score who showed a median OS of 4 months (p=0.93). Among ALBI score, G1 patients did not reach median OS, while the median OS of patients with G2 and G3 was 13 and 4 months respectively (p&lt;0.001). At Univariate analysis, histology (HR:1.22; p=0.021), bilirubin (HR:1.12; p&lt;0.001), albumin (HR:0.33; p&lt;0.001), CHILD-PUGH (HR:1.27; p&lt;0.001), ALBI (HR:2.91; p&lt;0.001), ECOG (HR:1.82; p&lt;0.001), surgery (HR:2.24; p=0.029) and systemic treatment (HR:2.57; p&lt;0.001) showed statistical differences. While only albumin (HR: 0.45; p=0.027), ECOG (HR: 1.49; p=0.006), systemic treatment (HR: 1.78; p=0.026) and ALBI score (HR: 1.71; p=0.032) remained predictors of OS. Conclusions: The study demonstrates that ALBI score presents a better prognostic and liver function stratification than CHILD-PUGH score in Mexican population.
Efficacy of the third-line chemotherapy in patients with advanced pancreatic cancer.
Authors: Bomi Kim, Jinwoo Ahn, Jae Hyup Jung, Kwangrok Jung, Jong-Chan Lee, Jin-Hyeok Hwang, Jaihwan Kim
Journal: Journal of Clinical Oncology (2023)

711 Background: First-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) have improved the survival outcomes of patients with advanced pancreatic cancer (APC) and nano-liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin is proven as the second-line agents. The current study aims to assess the efficacy of the third-line palliative chemotherapy in APC. Methods: Medical records were retrospectively reviewed in a single tertiary hospital between 2012 and 2020. The enrolled patients have APC who received the first and second-line chemotherapy. To fine the efficacy of the third-line chemotherapy, Kaplan Meier curve with cox-regression analysis was performed. Results: Of total 1,152 patients with pancreatic cancer, 362 patients were enrolled. Of these, 125 received the third-line chemotherapy and 238 received only supportive care after progression of the second-line chemotherapy. Median age at diagnosis was 60.3 years (range 36.0 – 86.0) and males were 52.0%. The first-line chemotherapy regimen was FOLFIRINOX (85, 68.0%), GNP (33, 26.4%), and others (7, 5.6%). The second-line chemotherapy regimen was GNP (55, 44.0%), FOLFIRINOX (34, 27.2%). As the third-line regimen, TS-1 and nal-IRI plus 5-FU/leucovorin were 73 (58.4%) and 20 (16.0%). The median overall survival (OS) from diagnosis was 18.0 months in all patients (95% CI, 14.6 – 21.4). The median OS after progression of the second-line therapy were 15.1 (95% CI, 12.8 – 17.5) and 8.5 weeks (95% CI, 7.7 – 9.4, p=0.007) between the patients with the third-line chemotherapy and supportive care only. Of the patients with the third-line chemotherapy, female showed the significant longer OS than male (12.4 (95% CI 10.2-14.6) vs. 6.6 weeks (95% CI 13.4-19.7), p=0.042). Conclusions: The current study suggested that proceeding with the third-line chemotherapy could be recommended in some patients. Females showed significantly more benefit than males. Further research on the selection for patient who will get the benefit from the third-line therapy is necessary.
Clinical outcomes in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in the pre-immunotherapy era.
Authors: Koen Zwart, Frederieke van der Baan, Matthew Dixon, Bryan Frantz, Cornelis J. A. Punt, Miriam Koopman, Geraldine R. Vink, Jeanine Roodhart
Journal: Journal of Clinical Oncology (2023)

65 Background: Data on clinical treatment outcomes of systemic non-immunotherapy in patients with MSI-H mCRC are limited due to low incidence. Real world data can support the interpretation of immunotherapy studies. Our aim is to provide insight on clinical outcomes of patients with MSI-H mCRC treated with systemic non-immunotherapy. Methods: We describe an observational cohort study with real-world data from the Netherlands Cancer Registry during 2015-2018 (N=383) and trial-based data from three prospective phase III first-line clinical trials: CAIRO, CAIRO2 and CAIRO3 (N=54). We investigated progression free survival (PFS) and overall survival (OS), which were defined as time from the start of first-line (PFS1/OS1), second-line (PFS2/OS2) and third-line (PFS3/OS3) of systemic non-immunotherapy until disease progression or death, respectively. Furthermore, we investigated objective response rate (ORR), which was defined as the proportion of patients with a complete or partial response as best response after first-line (ORR1), second-line (ORR2) and third-line (ORR3). Results: A total of 437 patients with MSI-H mCRC were analyzed. The proportion of patients receiving at least one line of systemic non-immunotherapy was 63%, 21% received two lines, and 5% received three lines. Patients receiving one line of therapy (N=270) had a median age of 69, 50% were female, 49% had a WHO performance score of 0, 70% had a right-sided tumor, 72% had synchronous mCRC, and 64% of those with synchronous mCRC received primary tumor resection. When known, 52% of patients harbored a BRAF mutation and 21% a RAS mutation. The results of OS, PFS, and ORR are summarized. Conclusions: To our knowledge these results provide insight on clinical outcomes in the largest observational cohort of patients with MSI-H mCRC treated with systemic non-immunotherapy to date. We showed a median PFS1 of 5.9 months and an OS1 of 14.1 months, which are in distinct contrast with patients in MSI-H mCRC trials receiving mono-immunotherapy in which a median PFS1 of 16.5 months was reached and a median OS1 was not reached after median follow-up of 44.5 months. Only 21% of patients in our observational cohort reached second-line of systemic non-immunotherapy and 5% third-line. Our results underline the importance and early access to immunotherapy in the MSI-H mCRC population. [Table: see text]